Case Analysis : Stem Cell Therapy for Parkinson's Disease

by Drs.Like Wu, Xiaojuan Wang and Bo Cheng

Introduction:

Parkinson's disease (PD) is a degenerative disorder of the central nervous system, PD is more commonly seen in the elderly. With most cases occurring after the age of 60, the sickness rate after the age of 65 is about 2%. Most cases are sporadic, less than 10% of the patients have family history of the disease.The main pathological change of PD is the death of dopamine-generating cells in the substantia nigra, a region of the midbrain; then it causes obvious dopamine DA to reduce in the corpus striatum. The cause of this pathological change is unknown. Many risk factors have been found, including: hereditary factors; environmental factors; aging factors; oxidative stress and so on.

The pathology of PD is characterized by the accumulation of a protein called alpha-synuclein into inclusions called Lewy bodies in the neurons, and also from insufficient formation and activity of dopamine produced in certain neurons within parts of the midbrain. More than 50% of the dopaminergic neurons die and reduce DA more than 80%. Other systems can have obvious damage as well, such as the cholinergic neuron in Meynert basal nuclei, noradrenergic neuron in locus ceruleus, and cerebral cortex, brainstem, spinal cord, neuron cell in peripheral autonomic nervous system.

Parkinson's disease has an insidious onset, meaning it is slow to progress. The common early stage symptom is a tremor and an awkward movement: maximal when the limb is at rest and disappearing with voluntary movement and sleep. It affects to a greater extent the most distal part of the limb and at onset it typically appears in only a single arm or leg, becoming bilateral later. The major symptoms are a rest tremor,bradykinesia,muscle rigidity and posture gait disorder. The non-motor symptoms, such as: depression, astriction, incontinentia urinae and dyssomnia are more and more noticeable in recent years, which have more affect than the motor symptoms. Patients commonly have no obvious abnormalities in blood tests, examination of cerebrospinal fluid, and/or the brain CT/MRI.

The symptoms of PD are chronic progressive and high heterogeneity. Different patients show different rates of progression, incurable. Medication has good curative effects for early stage patients, but movement complication may cause a decrease of life quality in medium stage patients, but even medication still has some effect on them. Medication has a poor effect for patients in the advanced stage, so it makes it hard to control symptoms. Patients may show catalepsy, where they cannot take care of themselves, even long-term bed-ridden patients have complications, such as respiratory failure.

Medications for symptomatic treatment has an effect on the early stages of PD, but cannot change the course of disease, neuron cells in the brain are continually missing, and medication cannot increase the quantity of cells, but the foundation of the treatment outcome has enough quantity of functioning cells, example: use madopar to replenish dopa, but failing because a large numbers of cells are missing.

Wu Stem Cells Medical Center found that transplanting neuron stem cells into the central nervous system can improve motor function and mental symptoms, because increasing the number of cells can excrete and use dopa, which increases the number of effective neuron cells that can slow down or stop the progression of PD as well.

Our Treatment Principle and Procedures

We use each patient's individual evaluation to determine which description of the disease they suffer from. Parkinson's disease symptoms are divided into five stages according to the Yahr system. The severity is measured using either the Webester or UPDRS scale.

The treatment for Parkinson's depends on which stage and scale the patient is measured at. The consensus comes from the conclusion of studies of medical reports during the past ten years as well as the information collected by our medical center through the use of META statistical analysis methods. The findings conclude that the treatment of mild to moderate patients, who are in the stage 1- 3 group, should use traditional medication. While the moderate to severe patients, who are in the stage 3- 5 group, or the ones whose drug treatment is ineffective, or have certain drug reactions such as on-off phenomenon, dyskinesia, can choose the following treatment options.

1. Striatum Stereotactic Pallidotomy: This kind of surgery has developed from the method called the opening cranium operation to the AC-PC stereotactic surgery method. Striatum stereotactic pallidotomy is used to destroy the bilateral thalami and pallidum step by step by placing electrodes into the brain.

The aims of this surgical method are to partly block cholinergic neuron channels and reduce the quantity of cerebral acetylcholine, as well as to keep the balance of dopamine transmitters to a low level, so that any tremors can be reduced.

Advantages include less trauma to the patient and the tremors are obviously reduced.

Disadvantages include some risks such as cerebral hemorrhage and this surgical method is not that effective for Parkinson's myotonia. The effectiveness of this method may only last for about one year and there is a risk of inducing dementia.

2. Stereotactic Technique of Deep Brain Stimulation (DBS): DBS requires the use of the opening cranium operation in order to implant the stimulated electrodes by using the CRW stereotactic heads, after a three dimensional image has been viewed by the computer, the coordinates of the nervous nuclei can be determined.

The purpose of the DBS pulse generator is to stimulate the functional dopaminergic neurons to release more dopamine in order to relieve the symptoms.

The advantages include lessening the amount of the dosage of dopamine medication and to improve the patient's quality of life.

The disadvantages include a limited amount of effective time for the curative effect and the patient can only undergo the operation one time. Long-term electrical stimulation of nerve cells plus the original toxicological effect will cause accelerated degeneration and death of the neurons. The disease develops quickly during the later stages.

3. Stem Cell Implantation during Brain Stereotactic Surgery: Stem cells are implanted to the target area by the use of needles through the stereotactic method mentioned above.
The purpose is cell replacement and to provide nutrition to the cells.

The advantage is that it is a biological treatment and therefore the operation can be done repeatedly if necessary and can increase the number of cells.

The disadvantages include difficulty in controlling the implanted cells and the outcome is not certain. There is also a risk of bleeding. Most patients are elderly and may have arteriosclerosis, adding to the complications. It is dangerous to do the deep brain centesis because of possible hemorrhaging. The quality of implanted stem cells is limited. Too many implanted cells may cause a local mass affect, such as the compression of a tumor. This kind of mechanical injury will cause damage to both brain tissue and stem cells. The inflammatory reaction caused by this injury could even lead to encephalitis. As the result of initial existing toxic environmental influences, the implanted stem cells cannot express their proper function. It is difficult for the stem cells to remain alive or to be controlled. Since there is a loss of brain cells, there will also be a loss of implanted stem cells.

4. Subarachnoid stem cell Implantation via lumbar puncture: Uses traditional and safe centesis. The cells are implanted into the cerebral spinal fluid through a puncture between the T3-4 or T4-5 using a special needle.

The purpose is to send the stem cells to the damaged areas in the spinal cord or brain.

The advantages include a safe and effective surgical operation. Patients will obtain positive results very soon. The analysis of the treatment results shows that the implanted stem cells successfully provide nutritional factors and there is also a positive psychological effect which together help to increase the chances of a successful outcome.

The disadvantage is that the therapeutic outcome is uncertain. The reasons include the cells' inability to pass through the cerebral spinal fluid- brain barrier easily. The implanted cells cannot effectively locate to the damaged areas.

5. Gene-Targeted stem cell implantation in patients with subarachnoid via lumbar puncture: Stem cells are implanted into the body by the methods described above. The quantity of implanted cells depends on the patient's individual medical needs. By using the CSF (cerebral spinal fluid) - brain barrier opening method, the stem cells will be absorbed into the tissues. Through softening scar tissue that is mainly formed by astrocytes in the damaged area, the astrocytes can be "rejuvenated" to express the characteristics of stem cells and generate signals making the implanted cells find the location of their gene expression.

Our ultimate goals are to relieve the symptoms and restore the lost neurological functioning. To do this, we use safe and effective technology to allow the implanted stem cells to accurately target the desired area. In the process, the amount of implanted cells is determined by the individual patient's needs. The patient's function can be expected to improve step by step until a stage is reached where the stem cell therapy can decrease or replace the dosage of traditional medication.

Our procedure is the easiest and safest possible. It's been proven to be effective in more than one hundred clinical applications. The procedure can be easily repeated as often as required.

Although this procedure is very easy and safe to perform, controlling the stem cells after the injection to make sure they are targeted to their desired location can be difficult. Despite this, our success rate for using this procedure for treating Parkinson's is very high.

The stem cells we use for the treatment of Parkinson's disease are always in compliance with the strict safety standards and regulations set by the SFDA. Theoretically, stem cells will finally differentiate into dopaminergic neurons or join in and assist dopamine transport channels, and then they will complete their reconstruction function. We believe that although any type of stem cells can be used if they meet the safety requirements; it is safer to use a single type of stem cell. Also we can use two kinds of cells to treat a disease. In treating Parkinson's disease, human retinal pigment epithelium (hRPE) is also used. It can release melanin and provide short-term nutrition. The improvement could be significant but it doesn't last long. On the hand, there is a risk that hRPE can form fibroblasts that may cause cancer, so we don't recommend this type of cell.

The mesenchymal stem cells derived from either bone marrow or umbilical cords can differentiate into nerve cells including dopamine-producing cells, and the obtained effect can last for a much longer time.

The patient is a 42-year-old male; he was presented with progressive trembling and slow movement for the past 2 years. He was diagnosed with Parkinson's disease. The patient was healthy before. He could take care of himself most of the time, but his work and quality of life have been negatively affected by the disease. He took anti-Parkinson's medication regularly, but his condition continued to worsen.

Admission PE: Bp 105/70 mmHg, HR 76/min. The heart, lungs and abdomen are all normal by physical examination. His lower limbs are not swollen. He is alert, speaking competently. His face is stiff and lacks expression. He has obvious aching in his left inner thigh. His memory, cognition and orientation are all ok. The bilateral pupils are equal and round, diameter is about 3.0mm, has good sensitivity response to light, and ocular movement is flexible. The binocular vision is slightly poor. The bilateral grain of the forehead and the naso-labial groove are symmetrical, the condition of the teeth and tongue are good, slight tremor of the lingualis. The bilateral soft palate is normal. His neck is flexible; when the patient shrugs, there is some weakness on the left side. The muscle force of the right limb is 5-degrees, and the muscle force of the left limb is also 5- degrees, holding power is 5-degrees. Both upper limbs have static tremors. The muscular tone of all four limbs has increased. The tendon reflexes of all four limbs are weakened. His bilateral abdominal reflexes can be induced by examination. Hoffmann signs with both sides are negative, jaw reflex of both sides is positive; Babinski signs with both sides are negative. Sensory system is good. There is some uncoordinated movement when attempting to point to his nose with his left hand and then switching to his right hand. The movements of the right side are more coordinated and flexible. He walks slowly and has difficulties standing when he shuts his eyes. Meningeal irritation signs are negative. The patient's Parkinson's UPDERS grade was 38 points when he was admitted.

Therapy objectives: To improve the movement of the patient's limbs, reduce tremors, and improve muscle force. After the treatment, it is expected that the patient's condition will be restored to normal.

Treatment procedure and results:

We gave the patient four mesenchyma stem cells implantation treatments, self stem cells activation treatments and anti-Parkinson's treatment. We eliminated oxyradicals in the patient's brain. The patient received treatments to improve circulation and nourish the neurons, together with daily rehabilitation training to promote the recovery of his motor functions. The patient's condition has shown good improvement: He has rich facial expressions, the strength in his left arm has increased noticeably. The patient's coordination and stability has greatly improved. The muscular tone in his left arm has been restored to normal. He has stated that he can participate in physical activities again and take care of himself. The quality of life and his ability to work has improved markedly. Upon leaving the hospital, the patient's Parkinson's UPDERS grade was 6 points.

Analysis:

Parkinson's disease (PD) is a kind of mesencephalon substantia nigra striatum system degeneration of dopaminergic neurons, resulting in the reduced secretion of the neurotransmitter dopamine. The patient develops a series of extrapyramidal conditions such as static tremors, stiffness in all four limbs, bradykinesia and bodily instability. At present, doctors treat this disease primarily by pharmacological means. Levodopa can improve the patient's clinical symptoms, but this is only one kind of neurotransmitter and cannot stop or reverse the course of the disease. If the patient takes levodopa for a long time, they will present with expiration phenomenon, switching phenomenon and other complications.

The surgical treatment, especially brain depth portion stimulation to treat PD also has certain effects. But brain depth portion stimulation treatment for autonomic nerve symptoms and cognition disorders has no obvious curative effect, and can cause intracranial hemorrhaging, epilepsy, depression, and other complications.

How to prevent or treat these complications? This is a difficult task for clinicians, and presently they do not have effective measures for preventing these complications. Fundamentally, neither the transmitter replacement therapy nor surgical procedures can improve the brain's environment and cannot increase the number of dopaminergic neurons. In fact, the multi-Parkinson's nerve toxicity and electrode's stimulation will cause the number of nerve cells to decrease further. Therefore seeking one truly effective type of treatment to increase the number of nervous system cells, in order to fight the cause of the disease, is vitally important.

Trauma,poisoning and pathological processes, such as hypoxia-ischemia-induced neuron loss, are irreversible. The embryonic stem cell's pluripotency and the adult stem cell's crosswise differentiation pluripotency have provided a new way of thinking regarding methods to treating Parkinson's disease. Through the transplantation of dopaminergic neurons to substitute metamorphic neurons, we can restore and improve the substantial nigra corpus striatum dopa system's integrity and its functioning. This is a remedial measure which has promising implications for the future. Activation of the patient's own neural stem cells can alleviate the disease. In recent years, we have treated Parkinson's disease by transplanting nerve stem cells and mesenchyma stem cells, obtaining good results. We can control the symptoms and block the progress of the disease.

We can also improve the movement of the limbs, giving the patient a chance to return to a normal quality of life.